Additional Investigation After the Muscle Biopsy Diagnosis

Her genetic testing revealed an abnormality in the LAMA2 gene, described as an heterozygous mutation in exon 2 with sequence variant defined as c.268delA (p.Ser90Alafs∗35) and deletion of exon 4-41 with approximate genomic locations 129, 397, 936 in intron 3 and 129, 753, 986 in intron 4.

Final Diagnosis

Merosin (laminin α2-chain) Deficient Congenital Muscular Dystrophy (MDC1A)

Patient Follow-up

The patient is currently followed at the pediatric neuromuscular clinic. A multidisciplinary clinic including neurology, pulmonology and neuromuscular therapists follow her on a regular basis. Her development is very slow. She is non-ambulatory and is developing thoracic scoliosis.

Discussion

Merosin deficient congenital muscular dystrophy is an autosomal recessive disease. It is one of the most common forms of congenital muscular dystrophy (CMD) and represents 10–40% of all cases in different CMD series [1–3]. Merosin is encoded by laminin alpha 2 chain gene (LAMA2) and is the predominant homologue of laminin α chain in the basal lamina of skeletal muscle fibers and Schwann cells in the nervous systems [4]. In skeletal muscle, merosin is a component of the extracellular matrix and connects to the sarcolemmal dystrophin complex through α-dystroglycan; its absence leads to myofiber degeneration. There is a wide spectrum of the disease with varying amounts of complete or partial merosin deficiency. Patients with MDC1A usually present at birth or early infancy with hypotonia and weakness [5]. Usually there are respiratory and feeding difficulties. Ophthalmoparesis particularly in upper gaze is common. There is elevation of CK level up to 10x the normal value. Increased T2 signal intensity in the white matter can be found on brain MRI, which is thought to be from abnormal myelination. Epilepsy can be present in 20% of patients and most patients are cognitively intact. Since laminin α2 is also present in Schwann cells, some patients develop a peripheral neuropathy. There is cardiac involvement in approximately 30% of the patients. Differential diagnosis consists of congenital myopathies and congenital myasthenic syndrome given the vertical gaze palsies as well as congenital muscular dystrophy.

The initial workup includes serum CK and brain MRI. Muscle biopsy is useful to differentiate merosin deficient congenital muscular dystrophy from other chronic active myopathies with similar clinical presentations. A specific genetic diagnosis relies on the gene mutation analysis. Muscle pathology of merosin deficient congenital muscular dystrophy is characterized by a complete or a partial deficiency of merosin with dystrophic characteristics, including myofiber necrosis, degeneration, regeneration, endomysial inflammation, and fibrofatty tissue replacement. The dystrophic changes alone do not differentiate different types of muscular dystrophies or other chronic active myopathies. An immunostaining panel encompassing the most common muscular dystrophy related proteins including merosin, α-dystroglycan, collagen IV, collagen VI, dystrophin epitopes, sarcoglycans, caveolin-3, dysferlin, and emerin should be performed. Merosin detection needs the use of two antibodies, the Millipore MAB1922 antibody to recognize the N-terminal of the 80-kDa protein fragment and the Leica/Novacastra NCL-MEROSIN antibody to recognize the C-terminal 300 kDa fragment. This aids in the cases of partial merosin deficiencies.

Management is multidisciplinary and includes neurology, cardiology, pulmonology and orthopedics similar to many of the congenital muscular dystrophies. The therapies using combinatorial approach of both protein therapy and gene therapy are currently being studied [6].

Pearls